Phosphonoacetic acid is a reasonably effective and rather specific antiherpesvirus agent. It interferes directly with the replication of herpesviruses because it is an inhibitor of the herpesvirus-induced DNA polymerase, an enzyme needed for the replication of herpesvirus DNA. An objective of the proposed research is to synthesize some derivatives of phosphonoacetate in which the phosphonoacetate is linked to amino acids, tripeptides, and nucleotides and to evaluate their antiherpesvirus activity. Hopefully, a derivative will be found that is a more effective antiherpesvirus agent than phosphonoacetate itself. At high concentrations, phosphonoacetate is cytotoxic, and at high concentrations, phosphonoacetate is an inhibitor of the cellular DNA polymerase alpha. An objective of the proposed research is to determine the mechanism by which phosphonoacetate is an inhibitor of the alpha-polymerase. Another objective of the proposed research is to test the hypothesis that phosphonoacetate is cytotoxic because it blocks DNA synthesis through specific inhibition of the alpha-polymerase. Phosphonoacetate-resistant and hopefully temperature-sensitive mutants of eukaryotic cells which should contain an altered alpha-polymerase will be isolated. These mutants will be used to evaluate the role that the alpha-polymerase plays in cellular DNA replication and repair.